Background on Cannabis

Marijuana describes the dried plant material of Cannabis sativa which includes Cannabis sativa subspecies sativa, Cannabis sativa subspecies indica, and various hybridizations of subspecies. The plant is an annual flowering herb that can be grown both outdoors and indoors (via hydroponic techniques using artificial lighting and nutrient rich water). The plant has both male and female forms. The highest concentration of THC resides in the buds of the pistillate flowers of the female plant – typically ranging 10-12%, whereas THC concentrations in leaves are about 1-2%, in stalks 0.1-0.3%, and in the roots less than 0.03%.1 Increasingly in recent years, cultivation of cannabis has moved towards cloning of female plants, allowing the buds to grow without fertilization from the male plant. This technique is termed sinsemilla (Spanish for “no seed”) and has allowed THC concentrations in cannabis to increase. Given the risk of exposures to wind disseminated pollen from male plants (or hermaphroditic plants), the majority of these grow operations are performed indoors using hydroponics although outdoor sinsemilla production is feasible.

In the United States, Cannabissativa can be sold in a variety of forms – most commonly as marijuana. Alternatively, active THC can be extracted from the plant to make either hashish or hash oil. Hashish is the extraction of resinous secretions using a sieve and yielding either a loose or pressed sticky powder. Hash oil results from the extraction of THC from plant material using an organic solvent (petroleum ether, ethanol, methanol, acetone, and more recently, butane). Higher concentration products can be solid at room temperature after solvents have evaporated and have been termed “dab,” “wax,” “honey,” “shatter,” “butane hash oil (BHO),” etc. Such products can be smoked in modified bongs or vaporizers. Further refined products can be used in edible products such as baked goods, candies, and soft drinks. Informal reports of hash oil products state THC concentrations upwards of 70-90%.2

As mentioned before, the principal active ingredient in cannabis is Δ9-tetrahydrocannabinol (THC). Numerous other cannabinoids (term used to describe compounds that activate cannabinoid receptors in the body) exist in marijuana with largely uncertain effects on the body. The other major cannabinoid often discussed is cannabidiol (CBD). Unlike THC, CBD does not activate any of the cannabinoid receptors directly but counteracts many of the stimulating effects of THC. CBD is being investigated as a potential therapy to treat seizures.3

Clinical and Adverse Effects of Cannabis

Acute cannabis intoxication ranges in clinical presentations from desired psychoactive effects to severe life-threatening respiratory depression. Most users of cannabis describe a sense of relaxation. Other reported effects include altered mood/sensation, slowed time, increased concentration, improved thinking, and increased appetite.4 In overdose, acute cannabis intoxication may lead to drowsiness/lethargy, tachycardia, agitation/irritability, confusion, vomiting, mydriasis, hallucinations/delusions, and dizziness/vertigo. Children less than 6 years old are more likely to have drowsiness/lethargy and respiratory depression.5 Multiple studies have reported children who required mechanical ventilation (machine to supply breaths) and/or intubation (tube inserted into the airway) to support their breathing.5-7 Serious cardiovascular and cerebrovascular events such as myocardial infarction, sudden cardiac death, and stroke have been associated with acute cannabis intoxication.8 However, the overall level of evidence to support these rare associations is low. Death after acute ingestion of cannabis is also rare. One death has been attributed to the ingestion of an edible THC infused cookie in March 2014 in Colorado. The 23-year-old man became erratic and hostile 2 hours after ingesting the cookie and jumped off a 4th floor balcony to his death.9 In reviewing United States poison center annual reports from 2011-2014, cannabis and analogs were implicated in 89 fatalities with exposures to other products and 11 fatalities with cannabis/analogs as single substance exposures.10-13

Cannabinoid hyperemesis syndrome (CHS) is an idiosyncratic reaction (occurs in some individuals but not others) to prolonged cannabis use. It is characterized by bouts of intense cyclic nausea and vomiting, epigastric (upper center) abdominal pain, and relief with hot showers/baths. Although patients with CHS believe continued cannabis use relieves the symptoms, ultimate resolution of the syndrome requires cessation of cannabis use.14 In Colorado after legalization of recreational cannabis, cyclic vomiting syndrome (a broader term that includes CHS) as a diagnosis in the emergency department (ED) increased from 41 per 113,266 ED visits to 87 per 125,095 ED visits.15

Driving while under the influence of cannabis increases the incidence of vehicular collisions. Blood concentrations of THC between 2-5 ng/mL are associated with driving impairment where the culpability of motor vehicle collisions increases with increasing concentrations of THC.16 Detectable blood concentrations of THC may have comparable risks to being responsible for motor vehicle collisions as with blood alcohol concentrations above 0.08%.17 In driving simulators, cannabis drivers compensate by driving slower and taking fewer risks yet are still less capable of handling complex tasks, are less capable of maintaining lane positions, and have increased response times.16

Cannabis use alters short-term memory and may be responsible for altered brain development. In animal studies, prenatal or in utero exposures to THC can re-calibrate sensitivity of reward systems to other drugs.17, 18 Studies have implicated cannabis as a gateway drug to the use of other illicit substances.18, 19 Adults who smoke cannabis regularly have fewer connections in the region of the brain that controls alertness, awareness, learning, and memory. Centers of the brain responsible for promoting habits, routines, and impulse control may also be impaired.17 In a longitudinal trial where individuals serve as their own control, heavier cannabis use led to lower IQ scores in early adulthood.20 The younger the age of cannabis initiation and heavier regular use of cannabis may both worsen brain development. As a result of both chronic use and short-term impairment of learning while intoxicated, cannabis use is associated with poorer educational outcomes and increased likelihood of dropping out.17

Finally, since the legalization of recreational cannabis in Colorado, there has been an increase in the number of patients who presented to the University of Colorado burn center in Aurora, Colorado secondary to the use of butane to extract THC from cannabis. A total of 31 admissions and 21 skin grafts (donor skin to replace areas of dead skin from burns) were required to treat these burns. Some burns involved greater than 70% total body surface area.15 The extraction process requires heating of the butane/THC mixture to yield the final hash oil product. During this process butane is ignited either from the heating source or from the individual lighting a marijuana cigarette.

Cannabis Use Disorder

Currently, cannabis is the most used illicit substance in the United States. In 2013, an estimated 19.8 million (7.5%) of Americans older than 12 years reported past month use of cannabis. The number of new users continues to increase by an average of 6,600 per day.21 To worsen the situation, the perceived risk of smoking cannabis in youths aged 12-17 years has declined from 54.6% in 2007 to 39.5% in 2013.21 Decreased perceived risk of cannabis use is further exaggerated in Colorado (where medical and recreational marijuana have been legalized) as compared to states without decriminalized medical marijuana.22

The official definition for substance use disorder was updated in 2013 in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The diagnosis of a substance use disorder is made when 2 or more of the following criteria are met over a 12-month period: (1) hazardous use, (2) social/interpersonal problems related to use, (3) neglected major roles to use, (4) legal problems, (5) withdrawal, (6) tolerance, (7) used larger amounts/longer, (8) repeated attempts to quit/control use, (9) much time spent using, (10) physical/psychological problems related to use, (11) activities given up to use, and (12) craving.23 Based on this definition, cannabis use disorder in the United States has a lifetime prevalence of 6.2% in 2013.24Of first time users, 8.9% will go on to develop cannabis use disorder in their lifetime. In comparison, lifetime cumulative probability of dependence is 67.5% for first time nicotine users, 22.7% for alcohol users, and 20.9% for cocaine users.25 The earlier cannabis use is initiated or the heavier the cannabis use, the higher the probability of lifetime diagnosis of cannabis use disorder. Teenagers have a 1 in 6 (17%) lifetime probability, and daily cannabis users have a 25-50% lifetime probability.18

The process of addiction in the brain for cannabis is similar to other illicit drugs of abuse. Cannabis use increases the amount of dopamine (signaling molecule) in the nucleus accumbens (area of the brain controlling reward signaling) similar to the natural process of rewarding and reinforcing positive behavior.26 Furthermore, chronic cannabis use is complicated by a punishing withdrawal syndrome similar to, albeit milder than, that of alcohol and nicotine. The withdrawal syndrome is characterized by 3 or more of the following: (1) irritability, anger or aggression, (2) nervousness or anxiety, (3) sleep difficulty (insomnia), (4) decreased appetite or weight loss, (5) restlessness, (6) depressed mood, (7) physical symptoms causing significant discomfort from at least one of the following: stomach pain, shakiness/tremors, sweating, fever, chills, headache.27

Evolution of Δ9-tetrahydrocannabinol Concentrations

Cannabis in the United States is federally classified as a Schedule I substance. Cannabis research through federal funding is closely controlled by the National Institute on Drug Abuse (NIDA), who sponsors research on cannabis and cultivation of Cannabissativa through the National Center for Natural Products Research (NCNPR) at the University of Mississippi. In cooperation with the Drug Enforcement Administration (DEA), NCNPR runs the Potency Monitoring Program for cannabis seized across the United States since the 1970s. The most recent publication by NCNPR tracked THC concentrations in confiscated cannabis from January 1, 1995 to December 31, 2014. The average THC concentration in cannabis increased over the study period with a small peak in 2012. The greatest contributor to this increase was the proportion of sinsemilla (seedless female plant buds) in relation to marijuana seized. Even in marijuana products, the proportion of buds (contains higher THC concentration) in comparison to loose material (including buds, leaves, and stems) increased. Sinsemilla accounted for less than 0.5% of the tested product in 1995, as compared to 80.5% in 2014. The average THC concentration of marijuana in 1995 was 3.95±1.74% and increased to 6.08±3.3% in 2014 with a peak concentration of 7.19±3.34% in 2007. The average THC concentration of sinsemilla in 1995 was 9.64±5.13% and increased to 13.18±6.39% in 2014 with a peak concentration of 14.5±6.38% in 2012.28 By interpreting the peak data in 2012, the upper 95th percentile THC concentration for sinsemilla was 27.3%. Unfortunately, the authors did not provide a range of concentrations in the samples tested. The THC concentrations of hashish and hash oil samples were about 40% and 54%, respectively, in 2014.28

The other interesting finding of the aforementioned study was the relative decrease of CBD concentration in comparison to the THC concentration. The ratio of THC:CBD concentrations remained stable between 10-20 until 2009 when the ratio increased dramatically to about 80 in 2014.28 The resulting products may be more stimulating and therefore more dangerous.

Pearls

Acute cannabis intoxication can range from desired psychoactive effects to severe life-threatening respiratory depression with the latter being more common in children.

Cannabinoid hyperemesis syndrome, characterized by bouts of intense cyclic nausea/vomiting and relief with hot showers/baths, may be increasing with decriminalization of medical and recreational cannabis.

Consider secondary injuries related to cannabis use and production including motor vehicle collisions and severe burns.

Average THC concentrations of marijuana in the United States have increased related to the cultivation technique of sinsemilla (seedless female buds), which can yield an average concentration of 14.5% THC.

References / Further Reading:

United Nations Office on Drugs, Recommended methods for the identification and analysis of cannabis and cannabis products, United Nations Publications: Vienna, 2009.

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